PERPETUATION OF NON-GENETIC CHANGES AT A TRANSGENE LOCUS IN C. ELEGANS
Jose, Antony M
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Development of a multicellular organism from a single cell or from a few cells in every generation relies on the reproducible expression pattern of genes. At the beginning of every generation in every organism, at least a single progenitor cell is necessary to produce the organism. This cell is subjected to reprogramming mechanisms that erase epigenetic information transmitted from the previous generation and as it develops, the organism goes through experiences that affect gene expression. Despite this, developmental processes give rise to nearly the same organism in the next generation, suggesting that the components in the cells are similarly regulated in every generation. How a complex organism can develop and reproduce its gene expression pattern using only the information present within the progenitor cell is not understood. Here, we describe an engineered genetic locus in the nematode worm C. elegans that shows robust transgenerational expression like many loci in the genome but, unlike other tested loci, can be uniquely susceptible to transgenerational silencing by one of two distinct processes. This locus could be silenced by double-stranded RNA (dsRNA) transported from neurons and could also be silenced when inherited solely from the male parent in a genetic cross. Each process could initiate transgenerational silencing within the germline that lasted for >25 generations. The two processes depended on distinct mechanisms to initiate silencing – while neuronal dsRNA required the conserved dsRNA importer SID-1 and the Argonaute RDE-1, mating-induced silencing required the Piwi-interacting Argonaute PRG-1. Both processes engaged the same germline Argonaute HRDE-1 to maintain heritable silencing suggesting that both processes trigger silencing independently but converge on the same pathway for maintenance. No other locus that was tested showed such indefinite silencing by either mechanism, suggesting that most loci are resistant to changes in gene expression. Thus, the discovery of a locus that is susceptible to transgenerational change provides us with the first instance of how a single change at a gene sequence can be used to explain evolution of gene regulation.